Last month, when Allergan’s $AGN once-touted pipeline star rapastinel crashed and burned a slate of pivotal depression studies, it looked like the experimental modulator of the NMDA receptor would be shrouded in a cloak of invisibility — but researchers may have found a way to rescue the experimental drug by repurposing it as a treatment for opioid dependence.
In the United States, the crisis of opioid abuse, misuse and overdose — from prescription painkillers, heroin, and synthetic opioids such as fentanyl — has reached epidemic proportions, causing 130 deaths every day, according to NIH estimates. Once in withdrawal, addicts are left to cope with a myriad of symptoms including anxiety, agitation, sleep problems, muscle aches, runny nose, sweating, nausea, vomiting, diarrhea and opioid cravings.
In order to manage these often debilitating symptoms, withdrawal is managed by substitution with a less powerful opioid, followed by gradual reduction or transition to maintenance therapy with FDA-approved medication-assisted treatment (MAT) drugs such as methadone, buprenorphine or naltrexone, which can have unpleasant and sometimes dangerous side effects and often must be used for months to avoid relapse. Although the process of tapering opioid consumption and using MAT to treat opioid addiction is standard-of-care, it sustains the brain changes that result in addiction in the first place, which can lead to relapse before treatment is completed, according to researchers who evaluated the use of rapastinel in opioid dependence.
The trial in rats tested the use of rapastinel versus ketamine — a commonly-used cat tranquilizer and party drug known as Special K or Kit Kat — which has been proposed as an alternative, non-opioid treatment for opioid withdrawal, but it has the potential for abuse, induces a trance-like state and can cause hallucinations. In fact, J&J’s $JNJ ketamine-based depression drug Spravato has already won FDA approval. Rapastinel binds to the same receptor as ketamine but at a different site, where it confers a milder effect.
The scientists first induced opioid dependence in male and female adolescent (between 28 and 30 days old) Sprague-Dawley rats by injecting them with morphine in increasing doses twice a day for five days. On day six, rats were injected with naloxone and withdrawal signs were quantified. The rats were then given either ketamine injections twice daily (n=12), rapastinel injections every other day (n=14), or saline injections (n=24). On day nine, when the rats were given naloxone to measure withdrawal signs, rapastinel-treated rats exhibited significantly fewer withdrawal signs than those treated with ketamine.
The findings suggest that treatment with rapastinel induced safer withdrawal, sans any serious side effects, during the critical first days in the effort to abstain from opioid use — and the scientists hypothesized this would lead to a decreased risk of opioid relapse.
“Rapastinel research for opioid dependency is currently only being done in rodents, but if the drug continues to have successful trials, it may enter clinical trials for use in humans,” said Julia Ferrante, an undergraduate at Villanova University who conducted the research with Cynthia Kuhn, professor of pharmacology and cancer biology at Duke University.
The researchers are looking to keep testing rapastinel to investigate its effect on the molecular level and to check whether it can reduce the risk of relapse. The drug has a long way to go before it crosses the finish line, but if approved it would likely be administered intravenously, possibly in an outpatient setting, Ferrante added.
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